Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.
Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.
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作者：
人类诱导多能干细胞（iPSC）的分离为人类疾病建模提供了一种新的策略。最近的研究报道了疾病特异性人iPSC的衍生和分化。然而，该领域的一个关键挑战是证明疾病相关的表型以及在iPSC中建模疾病发病机制和治疗的能力。家族性自主神经功能障碍（FD）是一种罕见但致命的周围神经病变，由IKBKAP转录延伸相关点突变引起。这种疾病的特征是自主神经元和感觉神经元的耗竭。由于缺乏合适的模型系统，FD对周围神经系统的特异性和神经元丢失的机制知之甚少。在这里，我们报告了患者特异性FD-iPSC的衍生和定向分化为包括外周神经元在内的所有三个胚层的细胞。纯化的FD-iPSC衍生谱系中的基因表达分析证明了IKBKAP在体外的组织特异性错误剪接。患者特异性神经嵴前体表达特别低水平的正常IKBKAP转录本，提示疾病特异性机制。FD发病机制的进一步特征在于转录组分析和基于细胞的测定，揭示了神经原性分化和迁移行为的显著缺陷。最后，我们使用FD-iPSCs来验证候选药物在逆转异常剪接和改善神经元分化和迁移方面的效力。我们的研究说明了iPSC技术在获得人类疾病发病机制和治疗方面的新见解的前景。
The isolation of human induced pluripotent stem cells (iPSCs) offers a novel strategy for modeling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy caused by a point mutation in IKBKAP involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood due to the lack of an appropriate model system. Here we report the derivation of patient specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC derived lineages demonstrates tissue specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell based assays revealing marked defects in neurogenic differentiation and migration behavior. Finally, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining novel insights into human disease pathogenesis and treatment.
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影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
影响因子：
64.5
作者：
Soldner F;Hockemeyer D;Beard C;Gao Q;Bell GW;Cook EG;Hargus G;Blak A;Cooper O;Mitalipova M;Isacson O;Jaenisch R
通讯作者：
Jaenisch R
DOI：
10.1073/pnas.0404700101
发表时间：
2004-08-24
影响因子：
11.1
作者：
Perrier, AL;Tabar, V;Studer, L
通讯作者：
Studer, L
影响因子：
64.8
作者：
Park, In-Hyun;Zhao, Rui;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
46.9
作者：
Chambers, Stuart M.;Fasano, Christopher A.;Papapetrou, Eirini P.;Tomishima, Mark;Sadelain, Michel;Studer, Lorenz
通讯作者：
Studer, Lorenz